European Journal of Cancer
Issue 12, 2008

Professor Emeritus Louis Denis (Oncology Centre Antwerp, Belgium) was an academic urologist who introduced transrectal ultrasonography to Europe. He was EJC’s first managing editor, is a past president of EORTC and secretary of the patient advocacy group, Europa Uomo. He is interested in new drug development and clinical research in urological oncology; one of his interests is the chemoprevention of prostate cancer. (See also EJC 2008 44:7 928-936)

How strong is the evidence that oestrogens may play a role in prostate cancer?

The story is both old and new. Ten years ago, it had already been suggested that the male foetus may be influenced by the mother’s oestrogen during the first week of foetal life and that this foetal imprinting may be involved in the development of prostate cancer decades later. Foetal imprinting has been accepted as a concept since it was discovered that the daughters of women who took diethylstilbestrol while pregnant were much more likely to develop vaginal cancer – which is extremely rare – 25 years later.

Similarly, in prostate cancer, differences in pregnant women’s oestrogen levels could possibly explain why African American men in the States have more disease than Caucasian men.

Recently it was reported (J Natl Cancer Inst 2008; 100:815-825) that gene alterations do not occur in all patients but a large amount of information on more than 6.000 genes implicated oestrogen as part of a molecular pathway that results in the fusion of two genes promoting prostate cancer. These fusions (TMPRSS2/ETS) were found in up to 60% of patients and were associated with an aggressive clinical phenotype.

This scientific argument will be easier to check than foetal imprinting, and it suggests that oestrogen might be a target in prevention of prostate cancer.

Isn’t this counterintuitive, since oestrogen has long been considered to be protective?

No, it is a question of dose. Oestrogens are powerful drugs and control prostate cancer growth.  However in this case they act by lowering serum testosterone via the hypothalamic pituitary hormonal axis.  Other hormonal treatments also have this effect; they act by lowering or blocking the male hormones in prostate cancer patients. Another successful chemopreventive agent is finasteride (which blocks the conversion of testosterone to the more potent dihydrotestosterone).  In a US National Cancer Institute (NCI) sponsored trial, the Prostate Cancer Prevention Trial (PCPT) finasteride was tested against placebo in more than 18,000 men aged 55 or over.  The original trial was stopped in 2003 because it looked like finasteride was encouraging high grade cancers.  However a recent reanalysis found no support for this thesis and confirmed that the drug reduced prostate cancer risk by up to 25% in tumours with Gleason scores 5, 6 and 7.

Ongoing studies with dutasteride, blocking the two isozymes of 5 alphareducatase, are promising in terms of future treatments (REDUCE trial).

How seriously are these suggestions being taken?

At the moment, something like 1250 studies on prostate cancer are in progress. This includes about 70 randomised trials on all kinds of drugs, most of which are not hormone therapies. And these therapies are not anti-oestrogens. The NCI is sponsoring 17 prospective randomised Phase II and III trials on prevention, and only one (GPX-006) is studying an anti-oestrogen.

How advanced is other work into the chemoprevention of prostate cancer?

In 2003, the European code against cancer (Ann Oncol 2003 14(7): 973-1005) written by Peter Boyle and a total of 42 experts concluded that there was no convincing evidence of effective chemoprevention in prostate cancer. The American Institute for Cancer Research’s 500 page report, Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective (April, 2008) lists the activities and drugs that might increase or decrease the risk of each cancer. But in prostate cancer they don’t believe that anything works apart from the general advice on physical activity and diet that would be true for any cancer. Lycopene (in tomatoes), selenium and vitamin E have been suggested but there’s no conclusive truth that they are effective.  We have to look for the active agents in our nutrition. Chemoprevention in prostate cancer is clearly underutilized and extensive research is needed to confirm the circumstantial evidence hypothesis of the promising agents.

Will this new suggestion give research a real boost?

All chemopreventive agents that have any effect seem to have some hormonal activity, but solving prostate cancer isn’t going to happen in a single quantum leap. The first problem in chemoprevention is that although by age 50, 50% of Western men have an indolent prostate cancer – and by the age of 80, it’s 80% – only 10% ever develop a clinical cancer in their lifetime. There’s a real danger of over-treatment and we can’t embark on chemoprevention unless we have an extremely safe product that will do the trick. Furthermore, studies usually last 15 years, so nothing is going to change overnight.